Process for the production of halogenated benzilic acid alkyl esters

ABSTRACT

Halogenated benzilic acid alkyl esters are prepared by oxidizing the corresponding halogenated diphenylacetic acid alkyl ester in a polar-aprotic solvent in the presence of a quaternary ammonium hydroxide.

United States Patent 3,700,720

Sprinzak I 1 Oct. 24, 1972 [54] PROCESS FOR THE PRODUCTION OF I [56]References Cited I-IALOGENATED BENZILIC ACID OTHER PUBLICATIONS ALKYLESTERS V Yair Sprinzak, Rehovoth, Israel Yeda Research and DevelopmentCo., Ltd., Rehovoth, Israel Filed: Oct. 20, 1969 Appl. No.: 867,890

Inventor:

Assignee:

Foreign Application Priority Data Oct. 21, 1968 Israel ..30 923 US. Cl...260/473 A Int. Cl... ..C07c 69/76 Field of Search ..260/520, 473 A Y.Sprinzak et al. J. Am. Chem. Soc., 85, 1-655 (1963).

Bemis et al., J. Am. Chem. Soc., 88 5491 (1966). Fiesen et al., OrganicChemistry," Rheinhold Publishing Corp. NY. (1956), Page 228.

Sprinzak, J. Am. Chem. Soc. 80 5449 (1958).

Primary Examiner-Lewis Gotts Assistant Examiner-John F. TerapaneAttorney-Ostralenk, Faber, Gerb & Sofien ABSTRACT I-Ialogenated benzilicacid alkyl esters are prepared by oxidizing the correspondinghalogenated diphenylacetic acid alkyl ester in a polar-aprotic-solventin the presence of a quaternary ammonium hydroxide.

13 Claims, No Drawings PROCESS FOR THE PRODUCTION OF HALOGENATEDBENZILIC ACID ALKYL ESTERS The present invention relates to a newprocess for the preparation of halogenated benzilic acid alkyl esters,especially for the preparation of 4,4- dibromobenzilic acid alkylesters.

Alkyl 4,4'-dichloro-, 4-chloro-4'-bromo and 4,4'dibromobenzilates areknown agents for killing insects and acarinae.

The processes utilized up to now for the preparation of halogenatedbenzilic acid alkyl esters having not been found to be satisfactory.Usually they require several steps of reaction which makes themexpensive, cumbersome and reduces the yield. Moreover, the productsobtained are not always very pure (Berichte 41, 56 (1908); Belgian Pat.No. 691105).

It is also known from the J.Am'.Chem.Soc. 85, 1656 (1963) that onoxidizing diphenyl acetic acid methyl ester at room temperature by meansof oxygen. in pyridine and in the presence of benzyltrimethylammoniumhydroxide, a mixture consisting of about 42 percent of diphenylhydroperoxyaceti'c acid methyl ester or benzilic acid (after theacidification), about 26 percent of benzophenone and about 5 percent ofbenzilic acid methyl ester is obtained. It has now been found that thelow yields of the desired benzilic acid ester are due to atoo lowconcentrationof the solution (about 7.5 percent) and to a too highconcentration of the benzyltrimethylammonium hydroxide (120 molepercent) which conditions favor the formation of the undesired diphenylhydroperoxyacetic acid methyl ester and benzophenone.

It is thus the object of the present invention to develop a process forthe preparation of halogenated benzilic acid alkyl esters, which givesexceptionally high yields and very pure end-products.

The process according to the present invention for the preparation ofhalogenated benzilic acid alkylesters of the general formula I I OH 1wherein g R represents alkyl having froml to 4 carbon atoms, Halrepresents chlorine or bromine,.and n and m represent 0 or 1 comprisespassing continuously oxygen or a gaseous mixture containing oxygen, inparticular air, while stirring, through a to 50 percent by weightsolution of a corresponding diphenylacetic acid' alkyl ester in apolar-aprotic solvent at temperatures ranging between -1 0 and 30 C andin the presence of at most 10 molepercent, calculated on said aceticacid ester, of a quaternary ammonium hydroxide of the general formu- RaR4 As lower alkyl R to R are meant alkyl radical having one to four,preferably one or two carbon atoms.

The oxidation is preferably performed at temperatures ranging from 0 to25 C. When oxygen is used the temperature should be kept rather low, e.g. about 0 C, whereas when air is used the preferred temperature lies atabout 25 C.

As quaternary ammonium hydroxide of formula II can be mentioned, forexample, tetramethylammonium hydroxide, benzyltrimethylammoniumhydroxide, benzyltriethylammonium hydroxide and phenyltrimethylammoniumhydroxide; tetramethylammonium hydroxide being preferred. The quaternaryammonium hydroxide must be used in amounts of less than 10 mole-percent,calculated on the molecular amount of the starting ester, the additionbeing made continuously or in portions. As solvents, polar-aproticsolvents, i.e. those which do not furnish protons, can be mentioned, forinstance pyridine, 2,4,6-trimethyl pyridine, a-picoline anddialkylformamides, preferably dimethylformamide. The preferredconcentration of the starting ester in the polar solvent ranges between15 and 30 percent by weight. I i The oxidation may be preferablyperformed with pure oxygen or with air. Whenair is used as oxidationmeans, the preferred rate of introducing the air during the oxidation isat least 4 liters of air per mole of diphenyl acetic acid ester and perminute. More than l2liters of air per mole and minute no longerinfluence the yield of the resultant benzilic acid ester. When 4 litersof air per mole and minute are used at about 25 C, the reaction timesvary between 30 minutes and 60 minutes depending on the stirring speed,e.g. of about 2,000 r.p.m. If 12 liters of air/mole/minute are used, thereaction time can be reduced to a value varying between 15 to 30 minutesdepending on the stirring speed. If less than 4 liters air/mole/minuteare used, considerably lower yields are obtained.

When air at a rate of at least 4 liters/mole/minute is employed, thequaternary'ammonium hydroxides of formula 11 are preferably used in anamount ranging between 1 and 3 mole' percent calculated on the molaramount of the starting diphenyl acetic acid ester. When pure oxygen isused, the velocity; may be greatly reduced, e.g. to a minimum of 0.25liters oxygen/mole/minute at 0 C. l-ler'e also an amount'of 1 to 3mole-percent of quaternary ammonium hydroxide is sufficient forobtaining very high yields of the endproducts. When using oxygen atabout 0 C, the necessary time for completing the reaction is 45 to 60minutes, and the stirring speed may bemuch lower, e. g. 500 r.p.m.

The starting materials used in the new process,-i.e. the halogenateddiphenylacetic acid alkyl esters and their preparation are known.

If desired, the benzilic acid alkyl esters obtained can be hydrolizedinto the corresponding benzilic acids in a known manner, e.g. by boilingthe ester with an aqueous-alcoholic solution of potassium hydroxide,thus yielding the potassium salt, which salt is then treated with amineral acid, e.g. sulfuric acid.

.The following examples illustrate the invention. The temperatures arein degrees Centigrade.

EXAMPLE 1 A solution of 7.68 g (0.02 mole) of methyl bis-4-bromophenylacetate in 32 ml of pyridine (concentration 19.7 percent byweight) was stirred and at the same time oxygen was passed through thesolution at a rate of 6 ml of oxygen per minute at 0. To the solutionwas added in the course of about 1 hour, 0.5 ml of a 25 percent aqueoussolution of tetramethylammonium hydroxide (6.8 mole-percent). After thistime 250 ml of oxygen (measured atroom temperature and normal pressure)had been absorbed, the reaction flask was flushed with nitrogen and thetemperature of the reaction mixture was brought to 25 in the course ofabout 20 minutes. The solvent was then distilled off at reducedpressure, water was added and distilled off to remove any residualsolvent. Fresh water was then added and the mixture was stirred at roomtemperature, whereupon the product crystallized. The crystals werefiltered off, washed with water and dried. There were obtained 7.78 g ofmethyl-4,4'-dibromobenzilate, m.p. 6569. After recrystallization fromisopropanol, the melting point was 74.575.5 (97.2 percent).

. EXAMPLE 2 The reaction was performed as in Example 1, replacing themethyl bis-4-bromophenylacetate by 7.95 g (0.02 mole) of ethylbis-4-bromophenylacetate. After removal of the solvent as described inExample 1, the oily product was diluted with benzene, the benzenesolution was washed successively with water, diluted hydrochloric acidand water. Finally, the benzene was distilled off, first at normalpressure and then at reduced pressure. There were obtained 7.90 g ofethyl- 4,4-dibromobenzilate in the form of a thick oil, b.p. l69/0.065Torr (95.4 percent).

EXAMPLE 3 The reaction was performed as in Example 1, replacing themethyl bis-4-bromophenylacetate by 103 g (0.25 mole) of isopropylbis-4-bromophenylacetate in 300 ml pyridine. There were obtained 103 gof isopropyl 4,4'-dibromobenzilate, melting point 73-76 Afterrecrystallization from petroleum ether the melting point was 7980 (96.2percent).

EXAMPLE 4 EXAMPLE 5 The reaction was performed as in Example 3, exceptthat a-picoline was used as solvent. There were obtained 103 g ofisopropyl 4,4-dibromobenzilate, melting point 73-76 (96.2 percent).

EXAMPLE 6 A solution of 273g (0.66 mole) of isopropyl bis-4-bromophenyl-acetate in 1,000 g of dimethylforrnamide was stirred (500r.p.m.) at 0 C. Oxygen was bubbled through this solution at a rateof 266ml of 0 per mole of starting acetate and per minute, for 45 minutes. 26ml of a 10 percent aqueous solution of tetramethylammonium hydroxide(2.4 mole-percent) were added in three portions (11 ml at the beginning,1 1. ml after 22 minutes and 4 ml towards the end of the reaction time)to the solution, the temperature being always kept at 0 C by cooling.The resulting solution was treated as described in Example 1. In thismanner 256 g (90 percent) of isopropyl 4,4-dibromobe nzilate (meltingpoint 79-80) were obtained.

EXAMPLE 7 A solution of 103 g (0.25 mole) of isopropyl bis 4-bromophenylacetate in 400 ml of dimethylformamide was stirred vigorously(2,000 r.p.m.) at 25 C. Air was bubbled through this solution at a rateof 2 to 3 liters per minute (8 to 12 liters per mole and minute) and atthe same time 3.5 ml of a 10 percent aqueous solution oftetramethylammonium hydroxide were added dropwise to the solution,during a period of 18 to 20 minutes. This corresponds to a total amountof 1.5 mole-percent, calculated on the amount of the starting ester(0.25 mole). After the addition of the tetramethylammonium hydroxide wascompleted, the reaction mixture was stirred for another 5 minutes duringwhich period the introduction of air was continued. During the wholereaction, the temperature was maintained between 22 and 25 by gentlecooling. The solvent was then distilled off at reduced pressure and theend-product was recovered as described in the procedure of Example 1,whereby 104 g (97 percent of the theory) of pure isopropyl4,4'-dibromobenzilate, melting point 79-80 C, were obtained.

Similarly, the following compounds were prepared:

n-butyl 4,4' -dibromobenzilate b.p. l/0.006 Torr isobutyl4,4'-dibromobenzilate m.p. 74-75 methyl 4-bromo-4-chlorobenzilate m.p. 6l-63 ethyl 4-bromo-4-chlorobenzilate b.p. 165-167 /0.005 Torr V V In-propyl 4-bromo-4'-chlorobenzilate b.p. l70-175 /0.00l Torr isopropyl4-bromo-4'-chlorobenzilate m.p. 64-70 n-butyl 4-bromo-4-chlorobenzilateb.p. l87-l /0.001 Torr sec-butyl 4-bromo-4-chlorobenzilate m.p. 5556isobutyl 4-bromo-4-chlorobenzilate m.p. 66-67 What I claimis:

1. Process for the production of halogenated benzilic acid alkyl estersof Formula I DIED-EDWIN).

wmmmmwmw oo R (I) wherein m "A P R represents alkyl having from one tofour carbon atoms, and

Hal represents chlorine or bromine, and which comprises passingcontinuously oxygen or a gaseous mixture containing oxygen,while-stirring,

wherein R and R represent lower alkyl, and

R and R, independently represent lower alkyl, phen-j yl, benzyl orpiperidyl, and separating the benzilic acid alkyl ester, obtained fromthe oxidation of the halogenated diphenylacetic acid alkyl ester, fromthe reaction mixture. 2. Process according to claim 1, which comprisesconducting the oxidation in a 15 to 30 percent by weight solution of thehalogenated diphenylacetic acid ester in a polar-aprotic solvent.

3. Process according to claim 1, which comprises usingdimethyl-formamide, diethyl-formamide,

picoline, pyridine or 2,4,6-trimethyl-pyridine as polarv 5. Processaccording to claim 1, which comprises performing the oxidation by meansof oxygen at a temperature of about 0 C. y v

6. Process according to claim 1, which comprises using atetraalkylammonium hydroxide as quaternary ammonium hydroxide of FormulaII.

7. Process according to claim 6, which comprises usingtetramethylammonium hydroxide.

8. Process according to claim 1, which comprises using atrialkylbenzylammonium hydroxide or a trialkylphenylammonium hydroxideas quaternary am-' monium hydroxide of Formula II.

9.- Process according. to claim 8, which comprises usingtrimethylbenzylammonium hydroxide or trimethylphenylarnmonium hydroxide.

10. Process according to claim 1, which comprises maintaining, by theoxidation with air, an air velocity of at least 4 liters of air per moleof halogenated diphenylacetic ester and per minute.

11. Process according to claim 1 which comprises performing theoxidation in the presence of l to 3 mole-percent of the quaternaryammonium hydroxide, calculated on the halogenated diphenylacetic ester.

12. Process according to claim 1, which comprises maintaining, by theoxidation with oxygen, an oxygen velocity of at least 0.25 liters ofoxygen per mole of halogenated diphenylacetic acid and per minute.

13. Process according to claim 1, which comprises using abis-(4-bromophenyl)-acetic acid alkyl ester as starting compound. r

2. Process according to claim 1, which comprises conducting theoxidation in a 15 to 30 percent by weight solution of the halogenateddiphenylacetic acid ester in a polar-aprotic solvent.
 3. Processaccording to claim 1, which comprises using dimethyl-formamide,diethyl-formamide, Alpha -picoline, pyridine or 2,4,6-trimethyl-pyridine as polar-aprotic solvent.
 4. Process according toclaim 1, which comprises performing the oxidation by means of air asgaseous mixture containing oxygen at a temperature ranging between 15*and 25* C.
 5. Process according to claim 1, which comprises performingthe oxidation by means of oxygen at a temperature of about 0* C. 6.Process according to claim 1, which comprises using a tetraalkylammoniumhydroxide as quaternary ammonium hydroxide of Formula II.
 7. Processaccording to claim 6, which comprises using tetramethylammoniumhydroxide.
 8. Process according to claim 1, which comprises using atrialkylbenzylammonium hydroxide or a trialkylphenylammonium hydroxideas quaternary ammonium hydroxide of Formula II.
 9. Process according toclaim 8, which comprises using trimethylbenzylammonium hydroxide ortrimethylphenylammonium hydroxide.
 10. Process according to claim 1,which comprises maintaining, by the oxidation with air, an air velocityof at least 4 liters of air per mole of halogenated Diphenylacetic esterand per minute.
 11. Process according to claim 1, which comprisesperforming the oxidation in the presence of 1 to 3 mole-percent of thequaternary ammonium hydroxide, calculated on the halogenateddiphenylacetic ester.
 12. Process according to claim 1, which comprisesmaintaining, by the oxidation with oxygen, an oxygen velocity of atleast 0.25 liters of oxygen per mole of halogenated diphenylacetic acidand per minute.
 13. Process according to claim 1, which comprises usinga bis-(4-bromophenyl)-acetic acid alkyl ester as starting compound.